We investigated the consistency of protection induced by a novel Vero cell culture–derived seasonal influenza vaccine in the United States in 2008–2009. Only low levels of influenza activity were detected up until mid-January 2009, but activity increased in mid-January, peaking in mid-February, and remaining high until mid-March [10
]. The Vero-derived vaccine was consistently highly efficacious in preventing laboratory-confirmed influenza infection over this entire period (). Importantly, vaccine efficacy did not wane as the influenza season progressed; the weekly cumulative vaccine efficacy from the beginning of March onward was >78% for antigenically matched A/H1N1 strains, >77% for all antigenically matched strains, and >70% for all strains, irrespective of antigenic match. This is also demonstrated by the similarly high estimates of vaccine efficacy for antigenically matched strains in the first 3 months of the study (75.0%) compared with the period thereafter (85.0%). Because subjects were vaccinated in December, our study does not allow us to be certain that vaccine efficacy would be maintained at equally high levels to the end of an influenza season if vaccination were to be initiated at an earlier time point, as recommended by the CDC [11
]. However, as there was no indication of a reduction in vaccine efficacy up to 5 months after vaccination, it seems likely that earlier vaccination would also provide season-long protection.
Other studies assessing the longevity or consistency of vaccine efficacy against infection with seasonal influenza virus are limited. Historically, monovalent vaccines were reported to provide extended protection against the Hong Kong [12
] and Russian pandemic strain viruses [14
]. More recent studies have reported a trivalent live-attenuated influenza vaccine (LAIV) to provide stable levels of protection against CCII for up to 12 months in children [15
], and, in comparative studies, LAIV was relatively more efficacious than TIV in preventing CCII >4–8 months postvaccination compared to 0--4 months postvaccination [16
]. To our knowledge, the consistency of the protective efficacy of modern split or subunit TIVs compared with placebo has not previously been demonstrated in any population.
The cumulative vaccine efficacy estimates and efficacy up to or after 3 months reported here for the Vero-derived vaccine are similar to those determined for the entire study period, where vaccine efficacy was estimated to be 79% for antigenically matched A/H1N1 strains, 78.5% for all matched strains, and 71.5% for all strains, irrespective of antigenic match [1
]. It is difficult to compare absolute vaccine efficacy between independent studies due to a number of factors that cause heterogeneity between different studies, such as differences in virus strains, attack rate of circulating viruses, and clinical endpoints used; however, these efficacy estimates are in the upper range of those reported in other recent studies of seasonal influenza vaccines [2
] and similar to or higher than those reported in recent meta-analyses of TIV efficacy [19
A proportion of individuals were infected with influenza virus despite vaccination. However, our results demonstrate that the benefit of vaccination extends beyond the prevention of infection, because the majority of ILI symptoms in subjects with CCII were both milder and of shorter duration in vaccine recipients compared with placebo recipients (). In the cases of myalgia (P
.003), headache (P
.025), and fatigue (P
.013), the joint reduction in disease duration and severity was statistically significant (). The demonstration of statistical significance of VCIV in amelioration of disease is noteworthy in the context of the high efficacy of the vaccine in preventing influenza infection. This resulted in a small sample size for infected VCIV recipients and, consequently, a lower power of analysis, such that a larger effect is necessary to demonstrate statistical significance of disease amelioration than would be the case for a less efficacious vaccine. Amelioration of cough (P
.143) and oropharyngeal pain (P
.083) was also observed. The reduction in the severity and duration of these symptoms may also be clinically relevant, although the small sample size precluded the calculation of a statistically significant benefit.
Previous investigations into the potential of influenza vaccines to ameliorate disease in subjects with laboratory-confirmed influenza infection have been limited to a restricted selection of ILI symptoms, and few statistically significant reductions in the severity or duration of disease symptoms have been reported. A small number of studies have reported significant reductions in fever for TIV [21
] or LAIV [22
] recipients, or have shown a significant benefit of LAIV over TIV for the reduction of fever in children [23
] or older adults [24
]. Both TIV and LAIV have also been reported to reduce the rate of acute otitis media (AOM) in children [25
]; we did not investigate the occurrence of AOM because our study was of young healthy adults, and AOM is not a common symptom of influenza infection in this population. Prevention of infection and disease in vaccinated individuals also has the potential to benefit nonvaccinated contacts by preventing or reducing virus transmission. In this respect, the level of virus shedding in individuals who were infected despite vaccination would also be of interest. Our study did not include a quantitative assay for detection of virus in nasopharyngeal specimens; however, other studies have suggested that virus shedding may be less effectively reduced in recipients of TIV compared with recipients of LAIV [26
The conclusions of our study are subject to the limitations that are inherent to any post hoc analyses of study data. In addition, because no study arm with an egg-derived vaccine was included, we cannot make a direct comparison of vaccines produced in Vero cell culture or using standard technology. Other limitations are that due to the nature of the 2008–2009 influenza season, data are primarily for the A/H1N1 strain and only for adults aged 18–49 years because vaccination was recommended for all other populations in the United States at the time of the study. However, the potential clinical and socioeconomic benefits of vaccination in younger adults are also substantial [29
], as reflected in the global drive to increase vaccine coverage beyond traditional high-risk groups. In the United States, annual vaccination is now recommended for all individuals above the age of 6 months [32
], and it is the aim of the US Healthy People 2020 goals to achieve 80%–90% vaccine coverage [33
]. Improvements in influenza vaccine supply may be required to achieve these goals, and the availability of modern, robust, and flexible manufacturing technologies will facilitate this process [34
]. The present study makes an important contribution to a growing body of evidence supporting the use of cell culture technology for vaccine manufacture.